Method of using steroid acetonides

ABSTRACT

A method of treating topical inflammation in mammals by the administration of triamcinolone acetonide-21-valerate in a pharmaceutically acceptable carrier.

United States Patent 11 1 Sieger et a1.

METHOD OF USING STEROID ACETONIDES Inventors: George Madison Sieger,Montvale, N.J.; Walter Shultz, Spring Valley, N.Y.; Charles Krieger,Clifton, N].

American Cyanamid Company, Stamford, Conn.

Filed: Dec. 7, 1971 AppL No.: 205,762

Assignee:

References Cited UNITED STATES PATENTS 1/1963 Spero 260/239.55 D

1451 Sept. 11, 1973 3,048,581 8/1962 Fried 260/239.55 D 2,838,499 6/1958Spero et a1 260/239.55 D 3,312,590 4/1967 Elks et a1. 424/243 3,312,5914/1967 Elks et a1. 424/241 3,147,249 9/1964 Ercoli et a1. 260/239.55 D3,152,154 10/1964 Ercoli et a1. 260/397.45 3,691,214 9/1972 Ercoli eta1. 260/397.45 3,694,471 9/1972 Ercoli et al. 260/397.45 3,422,1931/1969 Shapiro et a1 424/243 3,383,394 5/1968 Weber et al. 260/397.45

Primary Examiner-Shep K. Rose Attorney-Ernest Y. Miller et a1.

[57] ABSTRACT A method of treating topical inflammation in mammals bythe administration of triamcinolone acetonide-21- valerate in apharmaceutically acceptable carrier.

7 Claims, No Drawings 1 METHOD OF USING STEROID ACETONIDES DESCRIPTIONOF THE INVENTION It is well known that steroids can be used topicallyand their use in this manner has met with varying degrees of success.The need has existed for a more potent topically useful steroid. We havenow found that triamcinolone acetonide-2 l-valerate as the activecomponent in a topical composition is a highly effectiveanti-inflammatory agent. This compound is more effective than many usedin the past including triamcinolone acetonide as a topicalanti-inflammatory agent by the vasoconstriction assay.

The active component of the present composition, triamcinoloneacetonide-Zl-valerate, may be prepared by adding n-valeryl chloride to acooled, stirred solution of triamcinolone acetonide. The mixture issubsequently heated to refluxing temperature and allowed to cool to roomtemperature. The mixture is diluted with ice water and extracted with asolvent such as chloroform. The chloroform extract is treated withwater, dilute hydrochloric acid, dilute sodium bicarbonate and finallysaturated saline. The chloroform extract is evaporated under reducedpressure. The product is slurried with acetone/n-hexane (1:19).Filtration gives the product 9a-f1uoro-1 1B,21-dihydroxy-16a,l7a-(isopropylidenedioxy)- l ,4-pregnadiene-3,20-dione 21- valerate, hereindescribed as triamcinolone acetonide- 21-valerate.

This steroid product may be incorporated into a variety of conventionalpharmaceutical formulations providing topical preparations atconcentrations of, for example, 0.01 to 0.50 percent, topical ointmentsat similar concentrations or in lotions, etc.

The compositions containing the active component of this invention maybe any of the standard pharmaceutical topical preparations: solutions,suspensions, lotions, ointments, creams, unguents, sprays, powders,foams, etc. Excipients used in such preparations may include bufferssuch as phosphate, citrate, or tartrate buffers, surfactants such aspolyoxyethylene (20) sorbitan monooleate (polysorbate 80) which is acomplex mixture of polyoxyethylene ethers of mixed partial oleic estersof sorbitol anhydrides and oxylated tertiary octylphenol formaldehydepolymer, which is a surface tension reducing agent. Preservatives suchas methyl and propyl parabens, which are the methyl and propyl esters ofp-hydroxybenzoic acid, potassium sorbate, benzyl alcohol and the likecan be used. Oils, waxes, fats, etc. are useful as emollients andointment or emulsion bases such as petrolatum, wool fat (anhydrouslanolin), squalane, spermaceti, andthe like can also be useful.Stabilizers such as talc, clays, vegetable colloids,carboxymethylcellulose, carboxypolymethylene, and the like; and perfumesor fragrances such as lavender, lemon, gardenia, etc. may be founduseful. Such preparations may be packaged in pressure containers, andadding to appropriate forms a propellant such as trichlorofluoromethane, dichlorodifluoromethane, or 1,-2-dichloro-l,1,2,2-tetrafluoroethane which are commonly used.

Triamcinolone acetonide-Zl-valerate was tested in comparison with avariety of other steroids having known topical anti-inflammatoryactivityaccording to a method measuring vasoconstriction. This assay isdescribed in the following publications: Topical Activities ofBetamethasone Esters in Man, A. W. McKenzie and R. M. Atkinson, Archivesof Dermatology 89, 741-746 (1964). Method for Comparing PercutaneousAbsorption of Steroids", A. W. McKenzie and R. B. Stoughton, Archives ofDermatology 86, 608-610 (1962). Percutaneous Absorption of Steroids", A.W. McKenzie, Archives of Dermatology 86, 61 1-614 (1962).

The various compounds are prepared for testing by serial dilutions in 95percent alcohol to give concentrations of 1:10,000 to 116,250,000 at 5levels. Two hundredths of a milliliter of each dilution is applied tothe volar surface of the forearm of 10 normal human subjects.Triamcinolone acetonide at the same dilutions is applied to the otherforearm. The areas of application are occluded for 16-20 hours and thenobserved to determine whether vasoconstriction is present or absent, theintensity of the vasoconstriction is not graded.

The results appear in the Table hereinafter, wherein the relativepotencies of steroids vs. triamcinolone acetonide are given.

TABLE Relative Potencies of Steroids (vs. Triamcinolone Acetonide) inthe Human vasoconstriction Assay Relative Potency Compound(triamcinolone acetonide= 1.0) Triamcinolone acetonide-Zl- 2.6 valerateTriamcinolone-21 -valerate 0. 105 Triamcinolone- 1 G-acetate- 0.0121-valerate Triamcinolone- 1 6-valerate 0.021Triamcinolone-16-acetate-l7- 0.040 2l-methylorthovalerateTriamcinolone-16,17,21- 0.089 orthovalerate I 1,2-Dihydrotriamcinolone 1.6 acetonide-Zl-valerate Triamcinolone acetonide-Zl- 0.021 tert.butylacetate Triamcinolone acetonide-Zl-tetra- 0.72 hydropyranyl etherTriamcinolone-16,7l-cyclic car- 0.03

bonate-Z l -ethylcarbonate These results show that when compared totriamcinolone acetonide, triamcinolone acetonide-Zl-valerate is 2.6times more potent in the assay. All other steroids tested weresignificantly lower in activity and only one other showed activitygreater than triamcinolone acetonide.

SPECIFIC DISCLOSURE v The following examples describe the preparation oftriamcinolone acetonide- 2 1 -valerate and its use in various topicalpreparations. Parts are by weight unless otherwise indicated.

EXAMPLE 1 Preparation of 9a-Fluoro-l 1fl,21-dihydroxy-l6a,l 7a-(isopropyl-idenedioxy)- l ,4-pregnadiene-3,2 1 -dione 21-valerate' To astirred solution of 3.0 gm. (6.9 millimoles) of triamcinolone acetonidein 50 ml. of pyridine, cooled The chloroform extract is treated withwater, dilute hydrochloric acid, dilute sodium bicarbonate and finally,with saturated saline solution. The chloroform extract is dried overanhydrous magnesium sulfate overnight and then evaporated under reducedpressure to a solid. The solid is slurried with acetone/n-hexane (1:19),25 ml. The product is removed by filtration, giving 3.03 gm. (84.5percent yield) of colorless product. Evaporation of the filtrateafforded a second crop, 0.33 gm. (total yield 93.5 percent).Crystallization from acetone/n-hexane gives a sample exhibiting thefollowing properties: Melting point 262.5-263.5C. corrected Kofler hotstage; DTA, single endotherm 264C. corrected. I. R. v r 3390, 1754,1733, 1672, 1626, 1166, and 1058 cm; [01],, 93 (C .408, CHC] 1 dm);A,,,,,,"3 238mu (16,600). Purity by partition column chromatography 99percent. Analysis calculated for C ,,H O F: C, 67.16; H, 7.58; F. 3.66.Found: C, 67.15; H, 7.75; F, 3.82.

EXAMPLE 2 Topical Cream Formulations Containing Variable Percentages ofTriamcinolone acetonide-Zl-valerate Ingredient Percent Range(w/w)Triamcinolone acetonide-2 1 -valerate 0.01-0.5

Glyceryl monostearate NF l- Squalane 1-5 Polysorbate 60 l-5 Polysorbate80 U.S.P." 1-5 Spermaceti 5-20 Stearyl alcohol U.S.P. 5-20 Sorbitolsolution U.S.P. 1-10 Preservatives 3-5 Distilled water q.s. ad 100"Squalane 2,6,l0,15,l9,23-Hexamethyltetracosane PolysorbatePolyoxyethylene sorbitan monooleate The ingredients are mixed in aconventional manner for preparing a pharmaceutical topical creamproviding a white cream which may contain for example, depending uponselected percentage of ingredients, such steroid percentages as 0.01,0.025, 0.1 or 0.5%.

EXAMPLE 3 Topical Ointment Formulations Containing Variable Percentagesof Triamcinolone acetonide-Zl-valerate Ingredient Percent Range (w/w)Triamcinolone acetonide-2l-valerate 0.01-0.5 White petrolatum U.S.P. 100

The ingredients are blended in a conventional manner, providing acolorless topical ointment, which may provide for example, such steroidpercentages as 0.01 0.025, 0.10 or 0.50 percent.

If desired, an antibacterial component such as neomycin may be added tothe formulation in amounts ranging from 0.1 percent to 3% (w/w), as thesulfate in a micronized form.

EXAMPLE 4 Topical lFoam Formulation Containing Triamcinoloneacetonide-21 valerate Weight Range (mg/Con- Distilled water Freon 12/114(40/60)" *Arlacel=Sorbitan monostearate 'Myrj= Polyoxyethylenederivative of fat forming fatty acids Dichlorodifluoromethane/l,2-dichloro-1 ,1 ,2,2-tetrafluoroethane 6-10 (gm/Container) 1.3-2.0(gm/Container) Ingredients are blended in a conventional manner, filledin containers and then pressurized with Freon.

EXAMPLE 5 Opthalmic Ointment Containing Variable Percentages ofTriamcinolone acetonide-Z l -valerate Ingredient Percent Range (w/w)Triamcinolone acetonide-Z l -valerate 0.01-0.50 Mineral oil, Light N.F.l-5 White petrolatum U.S.P. q.s. ad 100 Ingredients are blended in aconventional manner providing an off-white opthalmic or oticpreparation. Neomycin may be added as the micronized sulfate salt if anantibacterial ingredient is desired.

EXAMPLE 6 Topical Lotion Formulation Containing Variable Percentages ofTriamcinolone acetonide-Zl-valerate Ingredient Percent Range (w/w)Triamcinolone acetonide-Zl-valerate 0.01-0.5 Polawax PD 34 3-5 Volpo 200.5-2 Oleyl alcohol 1-5 Methylparaben 0. l 2-0.2 Propylparaben 0.02-0.06Squalane ]-5 Potassium Sorbate 0.05-0.25 Sorbitol soln. 5-10 Distilledwater q.s. ad

Volpo 20 Polyoxyethylene ether of oleyl alcohol *Polawax Higher fattyalcohols and ethylene oxide reaction products The ingredients areblended in a conventionalmanner to provide an opaque creamy lotion.

EXAMPLE 7 Topical Ointment Formulation Ingredient Percent Range (w/w)Triamcinolone acetonidc-Zl-valerate 0.01-0.5 Polyethylene glycol 400U.S.P. 5-20% White Petrolatum U.S.P. q.s. ad 100% The ingredients areblended providing a colorless topical ointment.

If desired, an antibacterial component such as neomycin may be added tothe formulation in amounts ranging from 0.1% to 3% (w/w), as the sulfatein the micronized form.

anti-inflammatory agent is incorporated in a topicalfoam.

5 6 5. A method in accordance with claim 1, wherein the effective amountof the steroid 9a-fluoro-l lfl,2lanti-inflammatory agent is incorporatedinan opthaliy q 17 i li di 4 4 omtment nadiene-3,20-dione 2l-valerate inassociation with a 6. A method in accordance with claim 1, wherein theanti-inflammatory agent is incorporated in a topical lotion.

7. A method of treating inflammation in a mammal Cent comprisingadministering topically to said mammal an pharmaceutically acceptablecarrier in which the steroid is present in from about 0.01 to about 0.50per

2. A method in accordance with claim 1, wherein the anti-inflammatoryagent is incorporated in a topical cream.
 3. A method in accordance withclaim 1, wherein the anti-inflammatory agent is incorporated in atopical ointment.
 4. A method in accordance with claim 1, wherein theanti-inflammatory agent is incorporated in a topical foam.
 5. A methodin accordance with claim 1, wherein the anti-inflammatory agent isincorporated in an opthalmic ointment.
 6. A method in accordance withclaim 1, wherein the anti-inflammatory agent is incorporated in atopical lotion.
 7. A method of treating inflammation in a mammalcomprising administering topically to said mammal an effective amount ofthe steroid 9 Alpha -fluoro-11 Beta ,21-dihydroxy-16 Alpha ,17 Alpha-(iso-propylidenedioxy)-1,4-pregnadiene-3,20-dione 21-valerate inassociation with a pharmaceutically acceptable carrier in which thesteroid is present in from about 0.01 to about 0.50 percent.